: Prostate cancer is the most frequently diagnosed malignancy and the second most common cause of cancer death among men in the US. Our general goals are two-fold, firstly to evaluate the strongest current hypotheses regarding the etiology of prostate cancer, and secondly to complete the establishment of a large, unique database consisting of repeated dietary assessments over several decades, archived blood specimens, and archived tumor tissue for immunohistochemistry, in-situ hybridization and DNA sequencing. This resource will allow for the rapid examination of future hypotheses as they emerge. In this proposal, we focus on interrelationships between dietary factors and hormonal levels, as well as genetic susceptibility factors. Utilizing archived blood samples collected in 1993-944 from 16,300 men in the ongoing Health Professionals Follow-Up Study, we will conduct a matched, nested case-control study based on 531 new cases projected from 1993 to 2000 to evaluate several hypotheses, all of which have substantial preliminary support. Firstly, we will examine whether an association between dietary fat and prostate cancer risk is mediated through specific types of fatty acids in red blood cell phospholipids, specifically, high levels of saturated fats, a-linolenic, and trans fatty acids and low levels of long-chain omega-3 fatty acids. We will also examine whether high fat, energy and protein intake increases risk of prostate cancer through hormonal mechanisms, involving both steroid hormones and insulin-like growth factor-1. Secondly, we will examine whether high intake of heterocyclic amines formed from the prolonged cooking of meat at high temperatures, as well as smoking history, are associated with prostate tumors possessing mutations in p53. Thirdly, we will evaluate whether increased plasma levels of specific carotenoids, particularly lycopene and a-tocopherol reduce risk of prostate cancer. Finally, we will examine the hormonal hypothesis of prostate carcinogenesis in substantial detail by assessing plasma testosterone, dihydrotestosterone, estradiol, and serum hormone binding globulin, as well as CAG repeats in the androgen receptor gene (possibly correlated with elevated transactivation of the androgen receptor), and TA repeats of the 5-a-reductase enzyme (which may influence mRNA stability and subsequently cellular levels of this enzyme). These studies will enhance our understanding of prostate carcinogenesis and provide a scientific foundation for future preventive efforts.